Modeling the Dynamics of Let-7-Coupled Gene Regulatory Networks Linking Cell Proliferation to Malignant Transformation.

Claude Gérard,Frédéric Lemaigre,Didier Gonze

doi:10.3389/fphys.2019.00848

Claude Gérard, Frédéric Lemaigre + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2019.00848

Copy DOI

Abstract

Let-7 microRNA controls the expression of proteins that belong to two distinct gene regulatory networks, namely, a cyclin-dependent kinase (Cdk) network driving the cell cycle and a cell transformation network that can undergo an epigenetic switch between a non-transformed and a malignant transformed cell state. Using mathematical modeling and transcriptomic data analysis, we here investigate how Let-7 controls the Cdk-dependent cell cycle network, and how it couples the latter with the transformation network. We also assess the consequence of this coupling on cancer progression. Our analysis shows that the switch from a quiescent to a proliferative state depends on the relative levels of Let-7 and several cell cycle activators. Numerical simulations further indicate that the Let-7-coupled cell cycle and transformation networks mutually control each other, and our model identifies key players for this mutual control. Transcriptomic data analysis from The Cancer Genome Atlas (TCGA) suggests that the two networks are activated in cancer, in particular in gastrointestinal cancers, and that the activation levels vary significantly among patients affected by a same cancer type. Our mathematical model, when applied to a heterogeneous cell population, suggests that heterogeneity among tumors may in part result from stochastic switches between a non-transformed cell state with low proliferative capability and a transformed cell state with high proliferative property. The model further predicts that Let-7 may reduce tumor heterogeneity by decreasing the occurrence of stochastic switches toward a transformed, proliferative cell state. In conclusion, we identified the key components responsible for the qualitative dynamics of two networks interconnected by Let-7. The two networks are heterogeneously activated in several cancers, thereby stressing the need to consider patient’s specific characteristics to optimize therapeutic strategies.

Highlights

Let-7 microRNAs control two distinct gene regulatory networks (GRNs) that regulate cell cycling and malignant transformation of breast cancer cells (Johnson et al, 2007; Iliopoulos et al, 2009)
Let-7 being a component common to the cell cycle and transformation networks, we raise the following questions: how does Let-7 control the cyclin-dependent kinase (Cdk)-dependent cell cycle network? Does Let-7 play a coupling role between the cell cycle GRN and the transformation GRN, and can the two GRNs be combined into a larger network that impacts on cancer progression? We address these issues using experiment-based mathematical modeling of the GRNs and by analyzing transcriptomic data from The Cancer Genome Atlas (TCGA)
We focus on Let-7 and explore its potential role to couple both GRNs driving proliferation and malignant transformation

Summary

Introduction

Let-7 microRNAs control two distinct gene regulatory networks (GRNs) that regulate cell cycling and malignant transformation of breast cancer cells (Johnson et al, 2007; Iliopoulos et al, 2009). Starting from a non-transformed, quiescent, cell state, defined by high Let-7 and low cyclin B/Cdk1 levels, a transient Src signal induced by inflammation triggers a down-regulation of Let-7, eliciting the switch of the cell cycle network from a stable steady state to sustained oscillations (Figure 3A).

Results

Conclusion